Homo sapiens Protein: FLT4
InnateDB Protein IDBP-243794.6
Last Modified 2014-10-13 [Report errors or provide feedback]
Gene Symbol FLT4
Protein Name fms-related tyrosine kinase 4
Synonyms FLT41; LMPH1A; PCL; VEGFR3;
Species Homo sapiens
Ensembl Protein ENSP00000377016
InnateDB Gene IDBG-62355 (FLT4)
Protein Structure
UniProt Annotation
Function Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3- kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr- 185', and of AKT1 at 'Ser-473'. {ECO:0000269PubMed:11532940, ECO:0000269PubMed:15102829, ECO:0000269PubMed:15474514, ECO:0000269PubMed:16076871, ECO:0000269PubMed:16452200, ECO:0000269PubMed:17210781, ECO:0000269PubMed:19610651, ECO:0000269PubMed:19779139, ECO:0000269PubMed:20224550, ECO:0000269PubMed:20431062, ECO:0000269PubMed:20445537, ECO:0000269PubMed:21273538, ECO:0000269PubMed:7675451, ECO:0000269PubMed:8700872, ECO:0000269PubMed:9435229}.
Subcellular Localization Cell membrane; Single-pass type I membrane protein. Cytoplasm. Nucleus. Note=Ligand-mediated autophosphorylation leads to rapid internalization.Isoform 1: Cell membrane; Single-pass type I membrane protein. Note=Ligand-mediated autophosphorylation leads to rapid internalization.Isoform 2: Cell membrane; Single-pass type I membrane protein.Isoform 3: Secreted. Cytoplasm.
Disease Associations Lymphedema, hereditary, 1A (LMPH1A) [MIM:153100]: A chronic disabling condition which results in swelling of the extremities due to altered lymphatic flow. Patients with lymphedema suffer from recurrent local infections and physical impairment. {ECO:0000269PubMed:10835628, ECO:0000269PubMed:10856194, ECO:0000269PubMed:9817924}. Note=The disease is caused by mutations affecting the gene represented in this entry.Hemangioma, capillary infantile (HCI) [MIM:602089]: A condition characterized by dull red, firm, dome-shaped hemangiomas, sharply demarcated from surrounding skin, usually presenting at birth or occurring within the first two or three months of life. They result from highly proliferative, localized growth of capillary endothelium and generally undergo regression and involution without scarring. {ECO:0000269PubMed:11807987}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.Note=Plays an important role in tumor lymphangiogenesis, in cancer cell survival, migration, and formation of metastases.
Tissue Specificity Detected in endothelial cells (at protein level). Widely expressed. Detected in fetal spleen, lung and brain. Detected in adult liver, muscle, thymus, placenta, lung, testis, ovary, prostate, heart, and kidney. {ECO:0000269PubMed:1327515, ECO:0000269PubMed:20224550, ECO:0000269PubMed:7675451}.
Number of Interactions This gene and/or its encoded proteins are associated with 17 experimentally validated interaction(s) in this database.
They are also associated with 4 interaction(s) predicted by orthology.
Experimentally validated
Total 17 [view]
Protein-Protein 17 [view]
Protein-DNA 0
Protein-RNA 0
Predicted by orthology
Total 4 [view]
Gene Ontology

Molecular Function
Accession GO Term
GO:0004672 protein kinase activity
GO:0004713 protein tyrosine kinase activity
GO:0004714 transmembrane receptor protein tyrosine kinase activity
GO:0005021 vascular endothelial growth factor-activated receptor activity
GO:0005515 protein binding
GO:0005524 ATP binding
GO:0016772 transferase activity, transferring phosphorus-containing groups
GO:0019838 growth factor binding
GO:0019903 protein phosphatase binding
Biological Process
GO:0001934 positive regulation of protein phosphorylation
GO:0001938 positive regulation of endothelial cell proliferation
GO:0001944 vasculature development
GO:0001945 lymph vessel development
GO:0001946 lymphangiogenesis
GO:0002040 sprouting angiogenesis
GO:0006468 protein phosphorylation
GO:0007169 transmembrane receptor protein tyrosine kinase signaling pathway
GO:0008284 positive regulation of cell proliferation
GO:0010575 positive regulation vascular endothelial growth factor production
GO:0010595 positive regulation of endothelial cell migration
GO:0018108 peptidyl-tyrosine phosphorylation
GO:0035924 cellular response to vascular endothelial growth factor stimulus
GO:0043066 negative regulation of apoptotic process
GO:0043410 positive regulation of MAPK cascade
GO:0046330 positive regulation of JNK cascade
GO:0046777 protein autophosphorylation
GO:0048010 vascular endothelial growth factor receptor signaling pathway
GO:0048514 blood vessel morphogenesis
GO:0060312 regulation of blood vessel remodeling
GO:0070374 positive regulation of ERK1 and ERK2 cascade
GO:0090037 positive regulation of protein kinase C signaling
Cellular Component
GO:0005576 extracellular region
GO:0005634 nucleus
GO:0005737 cytoplasm
GO:0005886 plasma membrane
GO:0005887 integral component of plasma membrane
GO:0043235 receptor complex
Protein Structure and Domains
InterPro IPR000719 Protein kinase domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR003598 Immunoglobulin subtype 2
IPR003599 Immunoglobulin subtype
IPR007110 Immunoglobulin-like domain
IPR009137 Vascular endothelial growth factor receptor 3 (VEGFR3)
IPR011009 Protein kinase-like domain
IPR013098 Immunoglobulin I-set
IPR020635 Tyrosine-protein kinase, catalytic domain
PFAM PF00069
Post-translational Modifications
SwissProt P35916
PhosphoSite PhosphoSite-P35916
UniProt Splice Variant
Entrez Gene 2324
UniGene Hs.646917
RefSeq NP_002011
OMIM 136352
HPRD 00636
EMBL AC122714 AK291679 AY233382 AY233383 EU826564 S66407 U43143 X68203 X69878
GenPept AAA85215 AAB28539 AAO89504 AAO89505 ACF47600 BAF84368 CAA48290 CAA49505